Treatment of central nervous system disorders with selective estrogen receptor modulators

ABSTRACT

The present invention provides a method of treating depression, mood swings, or Alzheimer&#39;s disease in a patient in need of such treatment by administering a selective estrogen receptor modulating compound of the formula  
                 
 
     in which R 1  and R 2  are independently hydroxy and alkoxy of one to four carbon atoms; and R 3  and R 4  are independently methyl or ethyl, or R 3  and R 4 , taken together with the nitrogen atom to which they are attached, form a pyrrolidino, methyl-pyrrolidino, dimethylpyrrolidino, piperidino, morpholino, or hexamethyleneimino ring.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/043,117, filed Apr. 9, 1997.

TECHNICAL FIELD

[0002] The present application relates to medical methods of treatment.More particularly, the present invention concerns the use of a class ofsubstituted benzo[b]thiophene compounds for the treatment of depression,mood swings, and Alzheimer's disease in patients in need thereof.

BACKGROUND OF THE INVENTION

[0003] In addition to the well documented effects of estrogen onreproductive tissue, bone and cholesterol metabolism in post-menopausalwomen, it is known that estrogen has a number of actions in the centralnervous system with both somatic and behavioral consequences.

[0004] In climacteric women, anxiety, depression, tension andirritability begin during the perimenopause and can be correlated toreduced estrogen levels. Estrogen replacement therapy has beenrecommended for the treatment of these symptoms (cf. J. Malleson,Lancet, 2: 158 (1953) and R. Wilson, et al., J. Am. Geriatric Soc.,11:347 (1963)).

[0005] The mechanism for the protective effects of estrogen againstdepression and mood swings is not well understood, but may be related tothe potential effects of estrogen on biogenic amines such as serotonin(cf. M. Aylward, Int. Res. Communications System Med. Sci., 1: 30(1973).

[0006] In the area of memory and cognition enhancement, S. Phillips, etal., Psychoneuroendocrinology, 17: 485-495 (1992) have reported that insurgically menopausal women given estrogen, scores in immediate anddelayed recall tests are greater than in similar women not givenestrogen. In a prospective cohort study in post-menopausal women, A. H.Paganini-Hill, et al., Am. J. Epidemiol., 140(3): 256-261 (1994)demonstrated that the risk of Alzheimer's disease was less in estrogenusers as compared with women who did not use estrogen. Furthermore, therisk of Alzheimer's disease decreased significantly with increasingdoses of estrogen and increased duration of estrogen use.

[0007] All of the these studies have lead to the growing perception inthe literature that estrogen replacement therapy is a promisingtreatment for central nervous system disorders such as depression andmood swings and of Alzheimer's disease in post-menopausal women. Thesepromising uses of estrogen replacement therapy are off-set, however, bythe disadvantages of long-term estrogen therapy associated with therisks of developing reproductive tissue cancers.

[0008] Women on estrogen replacement therapy develop endometrial cancerat rates three to six times higher than nonusers after three to sixyears of use; after ten years on estrogen replacement therapy, the riskratio increases to tenfold. A growing body of literature suggests thatlong-term (i.e. 10-15 years) causes a thirty to fifty percent increasein the risk of breast cancer.

[0009] Thus, there is a need for the development of compounds which arealternatives to estrogen possessing the same beneficial effects ondepression and mood swings and on the treatment of Alzheimer's disease,but which lack the detrimental effects on reproductive tissue.

BRIEF SUMMARY OF THE INVENTION

[0010] In accordance with the present invention, there is provided amethod of treating in a patient in need of such treatment, a centralnervous system disorder selected from depression, mood swings, andAlzheimer's disease comprising administering a therapeutically effectiveamount of a compound having the structure

[0011] or a pharmaceutically acceptable salt or pro-drug thereof.

[0012] In the structure shown above, R¹ and R² are independentlyselected from the group consisting of hydroxy and alkoxy of one to fourcarbon atoms.

[0013] R³ and R⁴ are independently selected from methyl or ethyl, or R³and R⁴, taken together with the nitrogen atom to which they areattached, form a pyrrolidino, methylpyrrolidino, dimethylpyrrolidino,piperidino, morpholino, or hexamethyleneimino ring.

[0014] The compounds of the present invention are selective estrogenreceptor modulators (SERM's), that is, compounds which produce estrogenagonism in one or more desired target tissues while producing estrogenantagonism and/or minimal (i.e. clinically insignificant) agonism inreproductive tissue such as the breast or uterus.

DETAILED DESCRIPTION

[0015] Throughout this specification and the appended claims, generalterms bear their usual meanings.

[0016] The term “alkyl” denotes a monovalent radical derived by removalof one hydrogen atom from methane, ethane, or a straight or branchedhydrocarbon and includes such groups as methyl, ethyl, propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl and the like.

[0017] “Alkoxy” means an alkyl group, as defined above, attached to theparent molecular moiety through an oxygen atom and includes such groupsas methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, sec-butoxy,iso-butoxy, tert-butoxy and the like. In the present invention, methoxyis the preferred alkoxy group.

[0018] The term “pro-drug,” as used herein means a compound of thepresent invention bearing a group which is metabolically cleaved in ahuman to produce a therapeutically active compound of the presentinvention. In particular, such pro-drug compounds include those in whicheither or both of the substituent groups R¹ and R² of the structureshown above are hydroxy groups which have been protected by apharmaceutically acceptable hydroxy protecting group which ismetabolically cleaved in the body to yield a corresponding monohydroxyor dihydroxy compound of the present invention. Hydroxy protectinggroups are described in Chapter 2 of T. W. Greene, et al., “ProtectiveGroups in Organic Synthesis,” Second Edition, John Wiley & Sons, Inc.,New York, 1991. Simple ether and ester groups are preferred as pro-drughydroxy protecting groups.

[0019] The term “patient” refers to a mammal which is in need oftreatment for mood swings, depression or Alzheimer's disease. It isunderstood that guinea pigs, dogs, cats, rats, mice, hamsters, rabbitsand primates, including humans, both male and female, are examples ofpatients within the scope of the meaning of the term.

[0020] Preferred compounds of the present invention include

[0021]6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidino-ethoxy)phenoxy]benzo[b]thiopheneor a pharmaceutically acceptable salt or pro-drug thereof; and

[0022]6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidino-ethoxy)phenoxy]benzo[b]thiopheneor a pharmaceutically acceptable salt or pro-drug thereof.

[0023] Preparation of Compounds of the Invention

[0024] The starting material for one route for preparing compounds ofthe present invention is prepared essentially as described by C. D.Jones in U.S. Pat. Nos. 4,418,068, and 4,133,814. The starting materialshave the formula 1:

[0025] wherein R⁵ and R⁶ are independently —H or a hydroxy protectinggroup.

[0026] The R⁵ and R⁶ hydroxy protecting groups are moieties which areintentionally introduced during a portion of the synthetic process toprotect a group which otherwise might react in the course of chemicalmanipulations, and is then removed at a later stage of the synthesis.Since compounds bearing such protecting groups are of importanceprimarily as chemical intermediates (although some derivatives alsoexhibit biological activity), their precise structure is not critical.Numerous reactions for the formation, removal, and reformation of suchprotecting groups are described in a number of standard works including,for example, Protective Groups in Organic Chemistry, Plenum Press(London and New York, 1973); Greene, T. W., Protective Groups in organicSynthesis, Wiley (New York, 1981); and The Peptides, Vol. I, Schrooderand Lubke, Academic Press, (London and New York, 1965).

[0027] Representative hydroxy protecting groups include, for example,-C₁-C₄ alkyl, -C₁-C₄ alkoxy, —CO—(C₁-C₆ alkyl), —SO₂—(C₄-C₆ alkyl), and—CO—Ar in which Ar is benzyl or optionally substituted phenyl. The term“substituted phenyl” refers to a phenyl group having one or moresubstituents selected from the group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, hydroxy, nitro, halo, and tri(chloro or fluoro) methyl. The term“halo” refers to bromo, chloro, fluoro, and iodo.

[0028] For compounds of formula 1, preferred R⁵ and R⁶ substituents aremethyl, isopropyl, benzyl, and methoxymethyl. Compounds in which R⁵ andR⁶ each are methyl are prepared via the procedure described in theabove-referenced Jones patent.

[0029] Compounds of formula 1 are also prepared in which the R⁵ hydroxyprotecting group is selectively removed, leaving R⁶ as a hydroxyprotecting group as part of the final product. The same is true in thecase in which the R⁶ hydroxy protecting group is selectively removed,leaving the R⁵ hydroxy protecting group in place. For example, R⁵ can beisopropyl or benzyl and R⁶ methyl. The isopropyl or benzyl moiety isselectively removed via standard procedures, and the R⁶ methylprotecting group is left as part of the final product.

[0030] As shown in Reaction Scheme I, the first steps of the presentprocess for preparing certain compounds of the present invention includeselectively placing a leaving group, R⁷ at the 3 position of a compoundof formula 1, to form a compound of formula 2, coupling the product ofthat reaction with a 4-(protected-hydroxy)phenol, 3, to form a compoundof formula 4, and selectively removing the R⁸ hydroxy protecting groupto form a compound of formula 5. In the sequence of steps shown inReaction Scheme I, the hydroxy protecting groups R⁵, R⁶ and R⁸ arechosen in such a manner that, in the final step, the hydroxy protectinggroup R⁸ can be selectively removed in the presence of hydroxyprotecting groups R⁵ and R⁶.

[0031] In the first step of Reaction Scheme I, an appropriate leavinggroup is selectively placed at the 3-position of the formula 1 startingmaterial via standard procedures. Appropriate R⁷ leaving groups includethe sulfonates such as methanesulfonate, 4-bromobenzenesulfonate,toluenesulfonate, ethanesulfonate, isopropanesulfonate,4-methoxybenzenesulfonate, 4-nitrobenzenesulfonate,2-chlorobenzenesulfonate, triflate, and the like, halogens such asbromo, chloro, and iodo, and other related leaving groups. However, toinsure proper placement of the leaving group, the named halogens arepreferred, and bromo is especially preferred.

[0032] The present reaction is carried out using standard procedures.For example, when the preferred halogenating agents are used, anequivalent of such a halogenating agent, preferably bromine, is reactedwith an equivalent of the formula 1 substrate, in a suitable solventsuch as, for example, chloroform or acetic acid. The reaction istypically run at a temperature from about 40° C. to about 80° C.

[0033] The reaction product from the above process step, a compound offormula 2, is then reacted with a 4-(protected-hydroxy)phenol, 3, toform compounds of formula 4 in which R⁸ is a selectively removablehydroxy protecting group. Generally, the 4-hydroxy protecting moiety ofthe phenol may be any known protecting group which can be selectivelyremoved without removing, in this instance, the R⁵ and, when present, R⁶moieties of a formula 3 compound. Preferred R⁸ protecting groups includemethoxymethyl, when R⁵ and/or R⁶ are not methoxymethyl, and benzyl. Ofthese, benzyl is especially preferred. The 4-(protected-hydroxy)phenolreactants are commercially available or can be prepared via standardprocedures.

[0034] The coupling reaction between compounds of formula 2 and those offormula 3 is known in the art as an Ullman reaction and is generally runaccording to standard procedures [see, e.g., “Advanced OrganicChemistry: Reactions, Mechanisms, and Structure,” Fourth Edition, 3-16,(J. March, ed., John Wiley & Sons, Inc. 1992); Jones, C.D., J. Chem.Soc. Perk. Trans. I, 4:407 (1992)].

[0035] In general, equivalent amounts of the two aryl substrates, in thepresence of up to an equimolar amount of a copper(I) oxide catalyst andan appropriate solvent, are heated to reflux under an inert atmosphere.Preferably, an equivalent of a formula 2 compound in which R⁷ is bromois reacted with an equivalent amount of 4-benzyloxyphenol in thepresence of an equivalent of cuprous oxide.

[0036] Appropriate solvents for this reaction are those solvents ormixture of solvents which remain inert throughout the reaction.Typically, organic bases, particularly a hindered base such as, forexample, 2,4,6-collidine, are preferred solvents.

[0037] The temperature employed in this step is generally sufficient toeffect completion of this coupling reaction, and will influence theamount of time required therefore. When the reaction mixture is heatedto reflux under an inert atmosphere such as nitrogen, thetime-to-completion is usually from about 20 to about 60 hours.

[0038] Following coupling of a compound of formula 2 with one of formula3, to form a formula 4 compound, formula 5 compounds are prepared byselectively removing the R⁸ hydroxy protecting group of a formula 4compound via well known reduction procedures. It is imperative that theselected procedure will not affect the R⁵ and, when present, R⁶ hydroxyprotecting groups.

[0039] When R⁸ is the preferred benzyl moiety, and R⁵ and, when present,R⁶ each are methyl, the present process step is carried out via standardhydrogenolysis procedures. Typically, the formula 4 substrate is addedto a suitable solvent or mixture of solvents, followed by the additionof a proton donor to accelerate the reaction and an appropriatehydrogenation catalyst.

[0040] Appropriate catalysts include noble metals and oxides such aspalladium, platinum, and rhodium oxide on a support such as carbon orcalcium carbonate. Of these, palladium-on-carbon, particularly 10%palladium-on-carbon, is preferred. Solvents for this reaction are thosesolvents or mixture of solvents which remain inert throughout thereaction. Typically, ethylacetate and C₁-C₄ aliphatic alcohols,particularly ethanol, is preferred. For the present reaction,hydrochloric acid serves as an adequate and preferred proton donor.

[0041] When run at ambient temperature and a pressure ranging form about30 psi (206.8 kilopascals) to about 50 psi 344.7 kilopascals), thepresent reaction runs quite rapidly. Progress of this reaction may bemonitored by standard chromatographic techniques such as thin layerchromatography.

[0042] As shown in Reaction Scheme II, upon preparation of a formula 5compound, it is reacted with a compound of formula

R⁴R⁵N—(CH₂)₂—Q  6

[0043] wherein R⁴ and R⁵ are as defined above, and Q is a bromo or,preferably, chloro, to form a compound of formula 7. The formula 7compound is then deprotected to form a compound of formula I.

[0044] In the first step of the process shown in Reaction Scheme II, thereaction is carried out via standard procedures. Compounds of formula 6are commercially available or are prepared by means well known to one ofordinary skill in the art. Preferably, the hydrochloride salt of aformula 6 compound is used. In a particularly preferred case of thecompounds of the present invention, 2-chloroethylpiperidinehydrochloride, is used.

[0045] Generally, at least about 1 equivalent of a formula 5 substrateis reacted with 2 equivalents of a formula 6 compound in the presence ofat least about 4 equivalents of an alkali metal carbonate, preferablycesium carbonate, and an appropriate solvent.

[0046] Suitable solvents for this reaction are those solvents or mixtureof solvents which remain inert throughout the reaction.N,N-dimethylformamide, especially the anhydrous form thereof, ispreferred. The temperature employed in this step should be sufficient toeffect completion of this alkylation reaction. Typically, ambienttemperature is sufficient and preferred. The present reaction preferablyis run under an inert atmosphere, particularly nitrogen.

[0047] Under the preferred reaction conditions, this reaction will runto completion in about 16 to about 20 hours. The progress of thereaction can be monitored via standard chromatographic techniques.

[0048] In an alternative process for preparing compounds of the presentinvention, shown in Reaction Scheme III below, a formula 5 compound isreacted in an alkali solution with an excess of an alkylating agent offormula 8:

Q—(CH₂)_(n)—Q′  8

[0049] in which Q and Q′ are the same or different leaving groups.Appropriate leaving groups are those mentioned above.

[0050] A preferred alkali solution for this alkylation reaction containspotassium carbonate in an inert solvent such as, for example, methyethylketone (MEK) or DMF. In this solution, the unprotected hydroxy group ofthe formula 5 compound is converted to a phenoxide ion which displacesone of the leaving groups of the alkylating agent.

[0051] This reaction proceeds best when the alkali solution containingthe reactants and reagents is brought to reflux and allowed to run tocompletion. When using MEK as the preferred solvent, reaction timesrange from about 6 hours to about 20 hours.

[0052] The reaction product from this step, a compound of formula 9isthen reacted with a compound of formula 10selected from 1-piperidine,1-pyrrolidine, methyl-1-pyrrolidine, dimethyl-1-pyrrolidine,4-morpholine, dimethylamine, diethylamine, diisopropylamine, or1-hexamethyleneimine, via standard techniques, to form compounds offormula 7. Preferably, the hydrochloride salt of a compound of formula10 is employed, with piperidine hydrochloride being particularlypreferred. The reaction is typically carried out with the alkylatedcompound of formula 9in an inert solvent, such as anhydrous DMF, andheated to a temperature in the range from about 60° C. to about 110° C.When the mixture is heated to a preferred temperature of about 90° C.,the reaction only takes about 30 minutes to about 1 hour. However,changes in the reaction conditions will influence the amount of timethis reaction needs to be run for completion. The progress of thisreaction step can be monitored via standard chromatographic techniques.

[0053] Certain preferred compounds of formula I are obtained by cleavingthe R⁵ and, when present, R⁶ hydroxy protecting groups of formula Icompounds via well known procedures. Numerous reactions for theformation and removal of such protecting groups are described in anumber of standard works including, for example, Protective Groups inOrganic Chemistry, Plenum Press (London and New York, 1973); Greene, T.W., Protective Groups in Organic Synthesis, Wiley, (New York, 1981); andThe Peptides, Vol. I, Schrooder and Lubke, Academic Press (London andNew York, 1965). Methods for removing preferred R⁷ and/or R⁸ hydroxyprotecting groups, particularly methyl and methoxymethyl, areessentially as described in the Examples, infra.

[0054] An alternative, and preferred, method for the preparation ofcompounds of the present invention is shown in Reaction Scheme IV. Inthe process shown there, the sulfur atom of a formula 2 compound isoxidized to form a sulfoxide, 11, which is then reacted with anucleophilic group to introduce the oxygen atom linker of formula Icompounds. The sulfoxide moiety of formula 12 compounds is then reducedto provide certain compounds of the present invention.

[0055] In the first step of this process, a compound of formula 2 isselectively oxidized to the sulfoxide, 12. A number of known methods areavailable for the process step [see, e.g., Madesclaire, M., Tetrahedron,42 (20); 5459-5495 (1986); Trost, B. M., et al., Tetrahedron Letters, 22(14); 1287-1290 (1981); Drabowicz, J., et al., Synthetic Communications,11 (12); 1025-1030 (1981); Kramer, J. B., et al., 34th National OrganicSymposium, Williamsburg, Va., Jun. 11-15, 1995]. However, many oxidantsprovide only poor conversion to the desired product as well assignificant over-oxidation to the sulfone. The preferred process,however, converts a formula 2 compound to a sulfoxide of formula 12 inhigh yield with little or no formation of sulfones. This processinvolves the reaction of a formula 2 compound with about 1 to about 1.5equivalents of hydrogen peroxide in a mixture of about 20% to about 50%trifluoroacetic acid in methylene chloride. The reaction is run at atemperature from about 10° C. to about 50° C., and usually required fromabout 1 to about 2 hours to run to completion.

[0056] Next, the 3-position leaving group, R⁷, is displaced by thedesired nucleophilic derivative of formula 13. Such nucleophilicderivatives are prepared via standard methods.

[0057] In this step of the process, the acidic proton of thenucleophilic group is removed by treatment with a base, preferably aslight excess of sodium hydride or potassium tertbutoxide, in a polaraprotic solvent, preferably DMF or tetrahydrofuran. Other bases that canbe employed include potassium carbonate and cesium carbonate.Additionally, other solvents such as dioxane or dimethylsulfoxide can beemployed. The deprotonation is usually run at a temperature betweenabout 0° C. and about 30° C., and usually requires about 30 minutes forcompletion. A compound of formula XIV is then added to the solution ofthe nucleophile. The displacement reaction is run at a temperaturebetween 0° C. and about 50° C., and is usually run in about 1 to about 2hours. The product is isolated by standard procedures.

[0058] In the next step of the present process, the sulfoxide of formula14 is reduced to a benzothiophene compound of formula I.

[0059] When desired, the hydroxy protecting group or groups of theproducts of the process shown in Reaction Scheme IV can be removed, anda salt of the product of any step of the process.

[0060] Pro-drug ester compounds of formula I are prepared by replacingthe 6- and/or 4′-position hydroxy moieties, when present, with a moietyof the formula —OCO(C₁-C₆ alkyl), or —OSO₂(C₂-C₆ alkyl) via well knownprocedures. See, e.g., U.S. Pat. No. 4,358,593.

[0061] For example, when an —OCO(C₁-C₆ alkyl) group is desired, a mono-or dihydroxy compound of formula I is reacted with an agent such as acylchloride, bromide, cyanide, or azide, or with an appropriate anhydrideor mixed anhydride. The reactions are conveniently carried out in abasic solvent such as pyridine, lutidine, quinoline or isoquinoline, orin a tertiary amine solvent such as triethylamine, tributylamine,methylpiperidine, and the like. The reaction also may be carried out inan inert solvent such as ethyl acetate, dimethylformamide,dimethylsulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone,methyl ethyl ketone, and the like, to which at least one equivalent ofan acid scavenger (except as noted below), such as a tertiary amine, hasbeen added. If desired, acylation catalysts such as4-dimethylaminopyridine or 4-pyrrolidinopyridine may be used. See, e.g.,Haslam, et al., Tetrahedron, 36:2409-2433 (1980).

[0062] These reactions are carried out at moderate temperatures, in therange from about −25° C. to about 100° C., frequently under an inertatmosphere such as nitrogen gas. However, ambient temperature is usuallyadequate for the reaction to run.

[0063] Acylation of a 6-position and/or 4′-position hydroxy group alsomay be performed by acid-catalyzed reactions of the appropriatecarboxylic acids in inert organic solvents. Acid catalysts such assulfuric acid, polyphosphoric acid, methanesulfonic acid, and the likeare used.

[0064] The aforementioned ester pro-drug compounds also may be providedby forming an active ester of the appropriate acid, such as the estersformed by such known reagents such as dicyclohexylcarbodiimide,acylimidazoles, nitrophenols, pentachlorophenol, N-hydroxysuccinimide,and 1-hydroxybenzotriazole. See, e.g., Bull. Chem. Soc. Japan, 38:1979(1965), and Chem. Ber., 788 and 2024 (1970).

[0065] Each of the above techniques which provide —OCO(C₁-C₆ alkyl)moieties are carried out in solvents as discussed above. Thosetechniques which do not produce an acid product in the course of thereaction, of course, do not call for the use of an acid scavenger in thereaction mixture.

[0066] When a formula I compound is desired in which the 6- and/or4′-position hydroxy group of a formula I compound is converted to agroup of the formula —OSO₂(C₂-C₆ alkyl), the mono- or dihydroxy compoundis reacted with, for example, a sulfonic anhydride or a derivative ofthe appropriate sulfonic acid such as a sulfonyl chloride, bromide, orsulfonyl ammonium salt, as taught by King and Monoir, J. Am. Chem. Soc.,97:2566-2567 (1975). The dihydroxy compound also can be reacted with theappropriate sulfonic anhydride or mixed sulfonic anhydrides. Suchreactions are carried out under conditions such as were explained abovein the discussion of reaction with acid halides and the like.

[0067] Preparation of Pharmaceutically Acceptable Salts of Compounds ofthe Present Invention

[0068] Although the free-base form of formula I compounds can be used inthe medical methods of treatment of the present invention, it ispreferred to prepare and use a pharmaceutically acceptable salt form.The compounds used in the methods of this invention primarily formpharmaceutically acceptable acid addition salts with a wide variety oforganic and inorganic acids. Such salts are also contemplated as fallingwithin the scope of the present invention.

[0069] The term “pharmaceutically acceptable salts” as used throughoutthis specification and the appended claims denotes salts of the typesdisclosed in the article by Berge, et al., J. Pharmaceutical Sciences,66(1): 1-19 (1977). Suitable pharmaceutically acceptable salts includesalts formed by typical inorganic acids such as hydrochloric,hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric,and the like as well as salts derived from organic acids, such asaliphatic mono and dicarboxylic acids, phenyl substituted alkanoicacids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids,aliphatic and aromatic sulfonic acids. Such pharmaceutically acceptableorganic acid addition salts include acetate, phenylacetate,trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate,o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate,phenylbutyrate, b-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate,caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate,glycollate, heptanoate, hippurate, lactate, malate, maleate,hydroxymaleate, malonate, mandelate, mesylate, nicotinate,isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, propiolate, propionate, phenylpropionate, salicylate,sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite,bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate,chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate,methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate,p-toluene-sulfonate, xylenesulfonate, tartarate, and the like. Preferredsalts are the hydrochloride and oxalate salts.

[0070] The pharmaceutically acceptable acid addition salts are typicallyformed by reacting a compound of formula I with an equimolar or slightmolar excess of acid. The reactants are generally combined in a mutualsolvent such as diethyl ether or ethyl acetate. The salt normallyprecipitates out of solution within about one hour to 10 days and can beisolated by filtration or the solvent can be stripped off byconventional means.

[0071] The pharmaceutically acceptable salts generally have enhancedsolubility characteristics compared to the compound from which they arederived, and thus are often more amenable to formulation as liquids oremulsions.

[0072] Pharmaceutical Formulations

[0073] The compounds of this invention are administered by a variety ofroutes including oral, rectal, transdermal, subucutaneus, intravenous,intramuscular, and intranasal. These compounds preferably are formulatedprior to administration, the selection of which will be decided by theattending physician. Thus, another aspect of the present invention is apharmaceutical composition comprising an effective amount of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, optionallycontaining an effective amount of estrogen or progestin, and apharmaceutically acceptable carrier, diluent, or excipient.

[0074] The total active ingredients in such formulations comprises from0.1% to 99.9% by weight of the formulation. By “pharmaceuticallyacceptable” it is meant the carrier, diluent, excipients and salt mustbe compatible with the other ingredients of the formulation, and notdeleterious to the recipient thereof.

[0075] Pharmaceutical formulations of the present invention are preparedby procedures known in the art using well known and readily availableingredients. For example, the compounds of Formula I, either alone, orin combination with an estrogen or progestin compound, are formulatedwith common excipients, diluents, or carriers, and formed into tablets,capsules, suspensions, solutions, injectables, aerosols, powders, andthe like.

[0076] The total active ingredients in such formulations comprises from0.1% to 99.9% by weight of the formulation. By “pharmaceuticallyacceptable” it is meant the carrier, diluent, excipients and salt mustbe compatible with the other ingredients of the formulation, and notdeleterious to the recipient thereof.

[0077] The formulations may be specially formulated for oraladministration, in solid or liquid form, for parenteral injection,topical or aerosol administration, or for rectal or vaginaladministration by means of a suppository.

[0078] The pharmaceutical compositions of this invention can beadministered to humans and other mammals orally, rectally,intravaginally, parenterally, topically (by means of powders, ointments,creams, or drops), bucally or sublingually, or as an oral or nasalspray. The term “parenteral administration” refers herein to modes ofadministration which include intravenous, intramuscular,intraperitoneal, instrasternal, subcutaneous, or intraarticularinjection or infusion.

[0079] Pharmaceutical compositions of this invention for parenteraladministration comprise sterile aqueous or non-aqueous solutions,dispersions, suspensions, or emulsions, as well as sterile powders whichare reconstituted immediately prior to use into sterile solutions orsuspensions. Examples of suitable sterile aqueous and non-aqueouscarriers, diluents, solvents or vehicles include water, physiologicalsaline solution, ethanol, polyols (such as glycerol, propylene glycol,poly(ethylene glycol), and the like), and suitable mixtures thereof,vegetable oils (such as olive oil), and injectable organic esters suchas ethyl oleate. Proper fluidity is maintained, for example, by the useof coating materials such as lecithin, by the maintenance of properparticle size in the case of dispersions and suspensions, and by the useof surfactants.

[0080] Parenteral compositions may also contain adjuvants such aspreservatives, wetting agents, emulsifying agents, and dispersingagents. Prevention of the action of microorganisms is ensured by theinclusion of antibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like. Prolonged absorption of injectable formulations may bebrought about by the inclusion of agents which delay absorption such asaluminum monostearate and gelatin.

[0081] In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug following subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension or crystalline or amorphous material of low water solubilityor by dissolving or suspending the drug in an oil vehicle. In the caseof the subcutaneous or intramuscular injection of a suspensioncontaining a form of the drug with low water solubility, the rate ofabsorption of the drug depends upon its rate of dissolution.

[0082] Injectable “depot” formulations of the compounds of thisinvention are made by forming microencapsulated matrices of the drug inbiodegradable polymers such as poly(lactic acid), poly(glycolic acid),copolymers of lactic and glycolic acid, poly (orthoesters), and poly(anhydrides) these materials which are described in the art. Dependingupon the ratio of drug to polymer and the characteristics of theparticular polymer employed, the rate of drug release can be controlled.

[0083] Injectable formulations are sterilized, for example, byfiltration through bacterial-retaining filters, or by presterilizationof the components of the mixture prior to their admixture, either at thetime of manufacture or just prior to administration (as in the exampleof a dual chamber syringe package).

[0084] Solid dosage forms for oral administration include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive component is mixed with at least one inert, pharmaceuticallyacceptable carrier such as sodium citrate, or dicalcium phosphate,and/or (a) fillers or extenders such as starches, lactose, glucose,mannitol, and silicic acid, (b) binding agents such ascarboxymethyl-cellulose, alginates, gelatin, poly(vinylpyrrolidine),sucrose and acacia, (c) humectants such as glycerol, (d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, silicates and sodium carbonate, (e) solution retardingagents such as paraffin, (f) absorption accelerating agents such asquaternary ammonium compounds, (g) wetting agents such as cetyl alcoholand glycerin monostearate, (h) absorbents such as kaolin and bentoniteclay, and (i) lubricants such as talc, calcium stearate, magnesiumstearate, solid poly(ethylene glycols), sodium lauryl sulfate, andmixtures thereof. In the case of capsules, tablets and pills, the dosageform may also contain buffering agents.

[0085] Solid compositions of a similar type may also comprise the fillin soft or hard gelatin capsules using excipients such as lactose aswell as high molecular weight poly(ethylene glycols) and the like.

[0086] Solid dosage forms such as tablets, dragees, capsules, pills andgranules can also be prepared with coatings or shells such as entericcoatings or other coatings well known in the pharmaceutical formulatingart. The coatings may contain opacifying agents or agents which releasethe active ingredient(s) in a particular part of the digestive tract, asfor example, acid soluble coatings for release of the activeingredient(s) in the stomach, or base soluble coatings for release ofthe active ingredient(s) in the intestinal tract.

[0087] The active ingredient(s) may also be microencapsulated in asustained-release coating, with the microcapsules being made part of apill of capsule formulation.

[0088] Liquid dosage forms for oral administration of the compounds ofthis invention include solution, emulsions, suspensions, syrups andelixirs. In addition to the active components, liquid formulations mayinclude inert diluents commonly used in the art such as water or otherpharmaceutically acceptable solvents, solubilizing agents andemulsifiers such as ethanol, isopropanol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethyl formamide, oils (in particular, cottonseed, ground nut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, poly(ethylene glycols), fatty acid esters ofsorbitol, and mixtures thereof.

[0089] Besides inert diluents, the liquid oral formulations may alsoinclude adjuvants such as wetting agents, emulsifying and suspendingagents, and sweetening, flavoring, and perfuming agents.

[0090] Liquid suspension, in addition to the active ingredient(s) maycontain suspending agents such as ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite clay, agar-agar, andtragacanth, and mixtures thereof.

[0091] Compositions for rectal or intravaginal administration areprepared by mixing one or more compounds of the present invention withsuitable non-irritating excipients such as cocoa butter, polyethyleneglycol or any suppository wax which is a solid at room temperature, butliquid at body temperature and therefore melt in the rectum or vaginalcavity to release the active component(s). The compounds are dissolvedin the melted wax, formed into the desired shape, and allowed to hardeninto the finished suppository formulation.

[0092] Compounds of the present invention may also be administered inthe form of liposomes. As is know in the art, liposomes are generallyderived from phospholipids or other lipid substances. Lipososomeformulations are formed by mono- or multilamellar hydrated liquidcrystals which are dispersed in an aqueous medium. Any non-toxic,pharmaceutically acceptable, and metabolizable lipid capable of formingliposomes can be used. The present compositions in liposome form cancontain, in addition to one or more active compounds of the presentinvention, stabilizers, excipients, preservatives, and the like. Thepreferred lipids are phospholipids and the phosphatidyl cholines(lecithins), both natural and synthetic.

[0093] Methods for forming liposomes are know in the art as described,for example, in Prescott, Ed., Methods in Cell Biology, Volume XIV,Academic Press, New York, N.Y. (1976), p. 33 et seq.

[0094] Method of the Present Invention

[0095] As discussed above, estrogen has a beneficial effect on moodswings and depression in post-menopausal women and has been creditedwith also having a beneficial effect in memory and cognition in elederlypatients. To be used as a therapeutic agent for such conditions, it maybe necessary to administer a drug to a patient over an extended periodof time. However, the drawbacks associated with the long-term use ofestrogen and the risk of attendant reproductive tissue cancers mitigateagainst such long-term use of estrogen. A substitute for estrogen musthave the beneficial effects of estrogen in the brain without theassociated detrimental effects in the breast and uterus. Moreover, sucha substitute must be capable of crossing the blood-brain barrier inorder to exert the desired effect.

[0096] The compounds of the present invention possess the desiredprofile, being selective estrogen receptor modulators (SERM's) withestrogen-like effects in certain tissues while lacking (or havingminimal agonistic effect) in the breast and uterus. Moreover, asdemonstrated by the following data, certain compounds of the presentinvention have been found to cross the blood-brain barrier and to haveeffective levels in brain following oral administration in laboratoryanimals.

[0097] Distribution of Compounds of the Invention Among Various Tissuesin the Female F344 Rat

[0098] Female Fischer 344 rats (approximately twelve weeks old) weregiven a single oral gavage dose of 5 mg/kg (30 mCi/kg) of ¹⁴C-labeled6-hydroxy-2-(4-methoxyphenyl)-3-[4-(piperidinoethoxy)phenoxy]benzo[b]thiophenehydrochloride in 50% PEG 300/50% water. Blood and tissues were collectedfrom three rats at each time point: just prior to dosing and at 2, 4, 8,and 24 hours after dosing. At each time point, the animals weresacrificed, blood samples were collected and the heparinized blood wascentrifuged and the plasma obtained. Following collection of the blooodsample in each case, the animals were perfused with 0.9% saline solutionand the brain, pituitary, femurs, ovaries, uterus and liver weresurgically removed and placed in separate containers. The brain wasfurther divided into the hypothalamus, hippocampus, cerebellum, andcerebral cortex. All samples were stored at −70° C.

[0099] The radioactivity of each sample was determined by liquidscintillation spectrometry. Plasma was counted directly, while the othertissues were either homogenized, digested, or oxidized prior to liquidscintillation counting. All tissues were weighed prior to treatment. Theliver and cerebrum were homogenized in 0.9% saline solution and analiquot of the homgenate was oxidized. The pituitary, hippocampus,hypothalamus, ovaries, uterus and cerebellum were oxidized directlyafter drying. The femur was digested with a mixture of 30% hydrogenperoxide, and concentrated perchloric acid (2/1 v/v) prior to liquidscintillation counting.

[0100] Samples were oxidized on a Packard Model307 Oxidizer and theresulting ¹⁴CO₂ trapped for liquid scintillation counting. Theradioactivity in each tissue sample was converted to nanogramequivalents per gram of tissue (specific activity=16.3 dpm/ng). The 0-24hour area under the curve (AUC₀₋₂₄ hr) was calculated for each sample.

[0101] A liver and cerebral cortex homogenate were analyzed by HPLC andUV detection at 315 nm to determine if the radioactivity in thesetissues was actually due to the drug initially dosed, to the primarymetabolite,6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(piperidinoethoxy)phenoxy]-benzo[b]thiophene,or there glucuronide conjugates. The cerebral cortex sample was obtainedeight hours after dosing and the liver samples were collected at fourand eight hours after dosing. The proteins in the homogenate wereprecipitated with acetonitrile and the supernate was evaporated todryness. The residue was reconstituted in mobile phase and injected ontoa SynChropak SCD-100 column with the initial mobile phase composed of60% 0.05 M KH₂PO₄, pH 7/17% methanol/17% acetonitrile. (v/v/v). Theretention times of the peaks from the homogenate were compared withthose obtained from authentic samples of6-hydroxy-2-(4-methoxyphenyl)-3-[4-(piperidinoethoxy)phenoxy]benzo[b]thiopheneand its metabolite,6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(piperidinoethoxy)phenoxy]benzo[b]-thiophene.

[0102] Radioactivity was found in all tissues as shown by the datapresented in Table 1. TABLE 1 Mean Pharmakokinetic Parameters forRadioactivity after a Single Oral Dose of¹⁴C-6-hydroxy-2-(4-methoxyphenyl)-3-[4-(piperidinoethoxy)phenoxy]benzo[b]-thiophene to Female F344 RatsC_(max)* T_(max) AUC* TISSUE (ng/ml) (hr) (ng hr/mL) Plasma 53 ± 6 7 653± 28 Cerebellum 425 ± 25 8 5442 ± 456 Cerebrum 488 ± 37 8 6259 ± 560Femur  523 ± 193 8  6458 ± 1666 Hippocampus 517 ± 37 8 7024 ± 660 Uterus609 ± 31 7 8093 ± 311 Hypothalamus  689 ± 112 8  8310 ± 1295 Ovaries1321 ± 187 7 16761 ± 1785 Pituitary 3203 ± 608 8 37666 ± 8829 Liver 3839± 669 7 51913 ± 3126

[0103] Examination of the data appearing in Table 1 indicate thatradioactive material was found in all tissues, with peak levels beingreached at 8 hours after dosing, with the exception of the liver wherepeak levels were reached at 4 hours after dosing. The lowestconcentrations were found in plasma and the highest in the liver. Boththe C_(max) and AUC₀₋₂₄ hr of radioactivity for the cerebellum,cerebrum, hippocampus, and hypothalamus were greater than those observedin the plasma, indicating that radioactivity distributed into the brainareas after administration of the parent compound,¹⁴C-6-hydroxy-2-(4-methoxyphenyl)-3-[4-(piperidinoethoxy)phenoxy]benzo[b]thiophene.Analysis of the cerebral cortex homogenate (described above) showed thatthe radioactivity was due both to the parent compound,¹⁴C-6-hydroxy-2-(4-methoxyphenyl)-3-[4-(piperidinoethoxy)phenoxy]benzo[b]thiopheneand its dihydroxy metabolite,¹⁴C-6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(piperidinoethoxy)phenoxy]benzo[b]thiophene,in a ratio of approximately 4:1. Peaks corresponding to the glucuronideconjugates of either the parent compound or its dihydroxy metabolitewere not observed in the HPLC chromatogram of the cerebral cortexhomogenate. The HPLC chromatogram of the liver homogenates did, however,show peaks whose retention times corresponded to the parent compound andits glucuronide conjugate.

[0104] Similarity of6-hydroxy-2-(4-methoxyphenyl)-3-[2-(piperidino-ethoxy)phenoxy]benzo[b]thiophene to Estrogen in the Hippo-campus

[0105] Estrogens, such as 17b-estradiol, regulate gene transcription bybinding to estrogen receptors (ER) which reside in the cytoplasm ofcertain cell populations. Ligand activation of the ER is a prerequisitefor nuclear transport of the complex where binding to a 13 base-pairpalindromic DNA consensus sequence (estrogen response element, or ERE)begins assembly of a transcriptional apparatus which culminates in theactivation of appropriate target genes. A variety of genes have beenidentified which are regulated by estrogen. These include cytoskeletalproteins, neurotransmitter biosynthetic and metabolic enzymes andreceptors, as well as other hormones and neuropeptides. ERE's have beenidentified in many estrogen-responsive genes including vitellogenin,c-fos, prolactin, and luteinizing hormone.

[0106] Of significance in the central nervous system, ERE-like sequenceshave been identified in p75^(ngr) and trkA, both of which serve assignaling molecules for the neurotrophins: nerve growth factor (NGF),brain derived nerve growth factor (BDNGF), and neurotrophin-3.

[0107] BDNF as well as NGF have been shown to promote the survival ofcholinergic neurons in culture. It is postulated that if theinteractions between neurotrophins and estrogens are important for thedevelopment and survival of basal forebrain neurons (which degenerate inAlzheimer's disease) then clinical conditions in which an estrogendeficiency exists (as after menopause) may contribute to a loss of thsesneurons.

[0108] A commonly employed model of estrogen depletion is theovariectomized adult rat. An experiment was conducted in ovariectomizedrats using differential mRNA display to determine the similaritiesand/or differences between a representative compound of the presentinvention,6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy)phenoxy]-benzo[b]thiophene,and estrogen at affecting gene expression in various brain regions.Specifically, female Sprague-Dawley rats, 6 weeks of age, wereovariectomized by the vendor. Following one week of acclimation to thelaboratory facility, daily subcutaneous injections of estradiol benzoate(0.03 mg/kg) or6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy)phenoxy]-benzo[b]thiophene(1 mg/kg), or vehicle (control) were initiated.

[0109] After five weeks of daily treatment, animals were sacrificed andtheir brains removed and hippocampi collected by microdissection. Thehippocampi were fast frozen in liquid nitrogen and stored at −70_C.Total RNA was prepared from pooled tissue from the appropriate treatmentand control groups and reverse transcribed using a 3′ oligonucleotideprimer which selected for specific mRNA (poly-A+) populations.Polymerase chain reactions (PCR) were carried out in a cocktailconsisting of: random 5′ oligonucleotides (10 base-pairs in length;total of 150), reaction buffer, Taq polymerase, and a ³²PdTCP.

[0110] After 40 rounds of amplification, the reaction products were sizefractionated on a 6% TBE-urea gel, dried and exposed to x-ray film. Theresulting mRNA display patterns were compared between treatment groups.6-Hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy)phenoxy]benzo[b]-thiophene produced a parallel pattern of gene activation orinactivation in the rat himmpocampus as that observed for estrogen.These data indicate that6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy)phenoxy]benzo[b]-thiophene produced an estrogen-like effect in the hippocampus, a keybrain region associated with Alzheimer's disease in humans.

[0111] Thus, administration of an effective amount of a compound of thepresent invention, especially6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy)phenoxy]benzo[b]-thiopheneand its primary metabolite,6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)phenoxy]benzo[b]-thiophenewould be useful in the treatment of Alzheimer's disease in a humanpatient.

[0112] As used herein, the term “effective amount” means an amount ofcompound of the present invention which is capable of alleviating thesymptoms of the conditions herein described. The specific dose of acompound administered according to this invention is determined by theparticular circumstances surrounding the case including, for example,the potency of the compound administered, the route of administration,the state of being of the patient, and the pathological condition beingtreated. A typical daily dose will contain a nontoxic dosage level offrom about 5 mg to about 600 mg/day of a compound of the presentinvention. Preferred daily doses generally will be from about 15 mg toabout 80 mg/day.

[0113] The exact dose is determined, in accordance with the standardpractice in the medical arts of dose titrating the patient; that is,initially administering a low dose of the compound, and graduallyincreasing the does until the desired therapeutic effect is observed.

[0114] The following examples are presented to further illustrate thepreparation of compounds of the present invention. The Examples are notto be read as limiting the scope of the invention as it is defined bythe appended claims.

[0115] NMR data for the following Examples were generated on a GE 300MHz NMR instrument, and anhydrous hexadeutero-dimethylsulfoxide was usedas the solvent unless otherwise indicated.

EXAMPLE 1

[0116] Preparation of[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiopheneOxalate Salt

[0117] Step a: Preparation of[6-methoxy-2-(4-methoxy-phenyl)-3-bromo]benzo[b]thiophene

[0118] To a solution of[6-methoxy-2-(4-methoxyphenyl)]benzo-[b]thiophene (27.0 g, 100 mmol)in1.10 L of chloroform at 60° C. was added bromine (15.98 g, 100 mmol)dropwise as a solution in 200 mL of chloroform. After the addition wascomplete, the reaction was cooled to room temperature, and the solventremoved in vacuo to provide 34.2 g (100%) of[6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene as a whitesolid. mp 83-85° C. ¹H NMR (DMSO-d₆) d 7.70-7.62 (m, 4H), 7.17 (dd,J=8.6, 2.0 Hz, 1H), 7.09 (d, J=8.4 Hz, 2H). FD mass spec: 349, 350.Anal. Calcd. for C₁₆H₁₃O₂SBr: C, 55.03; H, 3.75. Found: C, 54.79; H,3.76.

[0119] Step b): Preparation of[6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]thiophene

[0120] To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene (34.00 g, 97.4 mmol) in 60 mL of collidine under N₂was added 4-benzyloxyphenol (38.96 g, 194.8 mmol) and cuprous oxide(14.5 g, 97.4 mmol). The resultant mixture was heated to reflux for 48hours. Upon cooling to room temperature, the mixture was dissolved inacetone (200 mL), and the inorganic solids were removed by filtration.The filtrate was concentrated in vacuo, and the residue dissolved inmethylene chloride (500 mL). The methylene chloride solution was washedwith 3N hydrochloric acid (3×300 mL), followed by 1N sodium hydroxide(3×300 mL). The organic layer was dried (sodium sulfate), andconcentrated in vacuo. The residue was taken up in 100 mL of ethylacetate whereupon a white solid formed that was collected by filtration[recovered [6-methoxy-2-(4-methoxyphenyl)]benzo-[b]thiophene (4.62 g,17.11 mmol]. The filtrate was concentrated in vacuo, and then passedthrough a short pad of silica gel (methylene chloride as eluant) toremove baseline material. The filtrate was concentrated in vacuo, andthe residue crystallized from hexanes/ethyl acetate to provide initially7.19 g of[6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]-thiopheneas an off-white crystalline solid. The mother liquor was concentratedand chromatographed on silica gel (hexanes/ethyl acetate 80:20) toprovide an additional 1.81 g of product. Total yield of[6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]-benzo[b]thiophenewas 9.00 g (24% based on recovered starting material). The basic extractwas acidified to pH=4 with 5N hydrochloric acid, and the resultantprecipitate collected by filtration and dried to give 13.3 g ofrecovered 4-benzyloxyphenol. mp 100-103° C. ¹H NMR (CDCl₃): d 7.60 (d,J=8.8 Hz, 2H), 7.39-7.24 (m, 7H), 6.90-6.85 (m, 7H), 4.98 (s, 2H), 3.86(s, 3H) 3.81 (s, 3H). FD mass spec: 468. Anal. Calcd. for C₂₉H₂₄O₄S: C,74.34; H, 5.16. Found: C, 74.64; H, 5.29.

[0121] Step c): Preparation of[6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)phenoxy]benzo[b]thiophene

[0122] To a solution of[6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]thiophene(1.50 g, 3.20 mmol) in 50 mL of ethyl acetate and 10 mL of 1%concentrated hydrochloric acid in ethanol was added 10%palladium-on-carbon (300 mg). The mixture was hydrogenated at 40 psi for20 minutes, after which time the reaction was judged complete by thinlayer chromatography. The mixture was passed through Celite to removecatalyst, and the filtrate concentrated in vacuo to a white solid. Thecrude product was passed through a pad of silica gel (chloroform aseluant). Concentration provided 1.10 g (91%) of[6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)phenoxy]benzo[b]-thiopheneas a white solid. mp 123-126° C. ¹H NMR (DMSO-d₆) d 9.10 (s, 1H), 7.59(d, J=8.8 Hz, 2H), 7.52 (d, J=2.1 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 6.95(d, J=8.8 Hz, 2H), 6.89 (dd, J=8.8, 2.1 Hz, 1H), 6.72 (d, J=9.0 Hz, 2H),6.63 (d, J=9.0 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 3H). FD mass spec: 378.Anal. Calcd. for C₂₂H₁₈O₄S: C, 69.82; H, 4.79. Found: C, 70.06; H, 4.98.

[0123] Step d): Preparation of[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]-thiopheneOxalate Salt

[0124] To a solution of[6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)phenoxy]benzo[b]thiophene(1.12 g, 2.97 mmol) in 7 mL of anhydrous N,N-dimethylformamide under N₂was added cesium carbonate (3.86 g, 11.88 mmol). After stirring for 10minutes, 2-chloroethylpiperidine hydrochloride (1.10 g, 1.48 mmol) wasadded. The resultant mixture was stirred for 18 hours at ambienttemperature. The reaction was the distributed between chloroform/water(100 mL each). The layers were separated and the aqueous extracted withchloroform (3×50 mL). The organic was combined and washed with water(2×100 mL). Drying of the organic (sodium sulfate) and concentrationprovided an oil that was chromatographed on silica gel (2%methanol/chloroform). The desired fractions were concentrated to an oilthat was dissolved in 10 mL of ethyl acetate and treated with oxalicacid (311 mg, 3.4 mmol). After stirring for 10 minutes, a whiteprecipitate formed and was collected by filtration and dried to provide1.17 g (70%) overall of[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene as the oxalate salt. mp 197-200° C. (dec). ¹H NMR (DMSO-d₆) d7.60 (d, J=8.7 Hz, 2H), 7.55 (d, J=1.1 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H),7.06 (d, J=8.8 Hz, 2H), 6.91 (dd, J=8.8, 1.1 Hz, 1H), 6.87 (s, 4H), 4.19(broad t, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.32 (broad t, 2H), 3.12-3.06(m, 4H), 1.69-1.47 (m, 4H), 1.44-1.38 (m, 2H). FD mass spec: 489. Anal.Calcd. for C₂₉H₃₁NO₄S.0.88HO₂CCO₂H: C, 64.95; H, 5.80; N, 2.46. Found:C, 64.92; H, 5.77; N, 2.54.

EXAMPLE 2

[0125] Preparationof[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride salt

[0126] Treatment of the oxalate salt from Example 1 with aqueous base toproduce the free base, followed by reaction with diethyl ether saturatedwith HCl yielded the title salt, mp 216-220° C. ¹H NMR (DMSO-d₆) d 10.20(bs, 1H), 7.64 (d, J=8.7 Hz, 2H), 7.59 (d, J=1.5 Hz, 1H), 7.18 (d, J=9.0Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.96 (dd, J=9.0, 1.5 Hz, 1H), 6.92 (q,J_(AB)=9.0 Hz, 4H), 4.31 (m, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.43 (m,4H), 2.97 (m, 2H), 1.77 (m, 5H), 1.37 (m, 1H). FD mass spec: 489. Anal.Calcd. for C₂₉H₃₁NO₄S.1.0HCl: C, 66.21; H, 6.13; N, 2.66. Found: C,66.,46; H, 6.16; N, 2.74.

EXAMPLE 3

[0127] Preparation of[6-Methoxy-3-[4-[2-(1-pyrolodinyl)ethoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[0128] The title compound was prepared in the same manner as thecompound of Example 1, mp 95-98° C. ¹H NMR (DMSO-d₆) d 7.64 (d, J=9.0Hz, 2H), 7.58 (d, J=2.0 Hz, 1H), 7.18 (d, J=9.0 Hz, 1H), 7.00 (d, J=9.0Hz, 2H), 6.94 (dd, J=9.0, 2.0 Hz, 1H), 6.86 (s, 4H), 3.97 (t, J=6.0 Hz,2H), 3.83 (s, 3H), 3.76 (s, 3H), 2.73 (t, J=6.0 Hz, 2H), 2.51 (m, 4H),1.66 (m, 4H). FD mass spec: 477. Anal. Calcd. for C₂₈H₂₉NO₄S: C, 70.71;H, 6.15; N, 2.99. Found: C, 70.59; H, 6.15; N, 3.01.

EXAMPLE 4

[0129] Preparation of[6-Methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiopheneHydrochloride

[0130] The title compound was prepared in the same manner as thecompound of Example 1, mp 189-192° C. ¹H NMR (DMSO-d₆) d 10.55 (bs, 1H),7.64 (d, J=9.0 Hz, 2H), 7.58 (d, J=2.0 Hz, 1H), 7.19 (d, J=9.0 Hz, 1H),7.00 (d, J=9.0 Hz, 2H), 6.95 (dd, J=9.0, 2.0 Hz, H), 6.86 (s, 4H), 3.94(t, J=6.0 Hz, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 2.80 (t, J=6.0 Hz, 2H),2.66 (m, 4H), 1.53 (m, 8H). Anal. Calcd. for C₃₀H₃₃NO₄S.1.0HCl: C,66.71; H, 6.35; N, 2.59. Found: C, 66.43; H, 6.46; N, 2.84.

EXAMPLE 5

[0131] Preparation of[6-Methoxy-3-[4-[2-(1-N,N-diethylamino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiopheneHydrochloride

[0132] The title compound was prepared in the same manner as thecompound of Example 1, mp 196-198° C. ¹H NMR (DMSO-d₆) d 10.48 (bs, 1H),7.64 (d, J=9.0 Hz, 2H), 7.59 (d, J=2.0 Hz, 1H), 7.19 (d, J=9.0 Hz, 1H),7.00 (d, J=9.0 Hz, 2H), 6.97 (dd, J=9.0, 2.0 Hz, 1H), 6.87 (q,J_(AB)=9.0 Hz, 4H), 4.25 (m, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.54 (m,2H), 3.09 (m, 4H), 2.00 (m, 3H), 1.88 (m, 3H). Anal. Calcd. forC₂₈H₃₁NO₄S.1.5HCl: C, 63.18; H, 6.15; N, 2.63. Found: C, 63.46; H, 5.79;N, 2.85.

EXAMPLE 6

[0133] Preparation of[6-Methoxy-3-[4-[2-(morpholino)ethoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiopheneHydrochloride

[0134] The title compound was prepared in the same manner as thecompound of Example 1, mp 208-211° C. ¹H NMR (DMSO-d₆) d 10.6 (bs, 1H),7.63 (d, J=9.0 Hz, 2H), 7.60 (d, J=2.0 Hz, 1H), 7.20 (J=9.0 Hz, 1H),7.00 (d, J=9.0 Hz, 2H), 6.97 (dd, J=9.0, 2.0 Hz, 1H), 6.91 (q,J_(AB)=9.0 Hz, 4H), 4.29 (m, 2H), 4.08-3.91 (m, 4H), 3.82 (s, 3H), 3.77(s, 3H), 3.59-3.42 (m, 4H), 3.21-3.10 (m, 2H). Anal. Calcd. forC₂₈H₂₉NO₅S.1.0HCl: C, 63.09; H, 5.73; N, 2.65. Found: C, 63.39; H, 5.80;N, 2.40.

EXAMPLE 7

[0135] Preparation of[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[0136][6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride (10.00 g, 19.05 mmol) was dissolved in 500 mL of anhydrousmethylene chloride and cooled to 8° C. To this solution was added borontribromide (7.20 mL, 76.20 mmol). The resultant mixture was stirred at8° C. for 2.5 hours. The reaction was quenched by pouring into astirring solution of saturated sodium bicarbonate (1 L), cooled to 0° C.The methylene chloride layer was separated, and the remaining solidswere dissolved in methanol/ethyl acetate. The aqueous layer was thenextracted with 5% methanol/ethyl acetate (3×500 mL). All of the organicextracts (ethyl acetate and methylene chloride) were combined and dried(sodium sulfate). Concentration in vacuo provided a tan solid that waschromatographed (silicon dioxide, 1-7% methanol/chloroform) to provide7.13 g (81%) of [6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]-thiophene as a white solid.mp 93° C. ¹H NMR (DMSO-d₆) d 9.73 (bs, 1H), 9.68 (bs, 1H), 7.45 (d,J=8.6 Hz, 2H), 7.21 (d, J=1.8 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 6.84 (dd,J=8.6, 1.8 Hz, 1H (masked)), 6.81 (s, 4H), 6.75 (d, J=8.6 Hz, 2H), 3.92(t, J=5.8 Hz, 2H), 2.56 (t, J=5.8 Hz, 2H), 2.36 (m. 4H), 1.43 (m, 4H),1.32 (m, 2H). FD mass spec: 462. Anal. Calcd. for C₂₇H₂₇NO₄S: C, 70.20;H, 5.90; N, 3.03. Found: C, 69.96; H, 5.90; N, 3.14.

EXAMPLE 8

[0137] Preparation of[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiopheneOxalate Salt

[0138] The title compound was prepared in 80% yield from the free base,mp 246-249° C. (dec). ¹H NMR (DMSO-d₆) d 7.45 (d, J=8.6 Hz, 2H), 7.22(d, J=1.8 Hz, 1H), 7.05 (d, J=8.6 Hz, 1H), 6.87 (dd, J=8.6, 1.8 Hz, 1H(masked)), 6.84 (s, 4H), 6.75 (d, J=8.6 Hz, 2H), 4.08 (bt, 2H), 3.01(bt, 2H), 2.79 (m, 4H), 1.56 (m, 4H), 1.40 (m, 2H). FD mass spec 462.Anal. Calcd. for C₂₇H₂₇NO₄S.0.75HO₂CCO₂H: C, 64.63; H, 5.42; N, 2.64.Found: C, 64.61; H, 5.55; N, 2.62.

EXAMPLE 9

[0139] Preparation of[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[0140] The title compound was prepared in 91% yield by treatment of thecorresponding free base with HCl saturated diethyl ether, mp 158-165° C.¹H NMR (DMSO-d₆) d 9.79 (s, 1H), 9.74 (s, 1H), 7.40 (d, J=8.6 Hz, 2H),7.23 (d, J=2.0 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 6.86 (q, J_(AB)=9.3 Hz,4H), 6.76 (dd, J=8.6, 2.0 Hz, 1), 6.74 (d, J=8.6 Hz, 2H), 4.26 (bt, 2H),3.37 (m, 4H), 2.91 (m, 2H), 1.72 (m, 5 H), 1.25 (m, 1H). FD mass spec461. Anal. Calcd. for C₂₇H₂₇NO₄S.1.0HCl: C, 65.11; H, 5.67; N, 2.81.Found: C, 64.84; H, 5.64; N, 2.91.

EXAMPLE 10

[0141] Preparation of[6-Hydroxy-3-[4-[2-(1-pyrolidinyl)ethoxy]-phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[0142] The title compound was prepared from the product of Example 3 ina manner similar to that employed in Example 7 above; mp 99-113° C. ¹HNMR (DMSO-d₆) d 9.75 (s, 1H), 9.71 (s, 1H), 7.50 (d, J=9.0 Hz, 2H), 7.25(d, J=2.0 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 6.85 (s, 1H), 6.80 (dd,J=9.0, 2.0 Hz, 1H), 6.79 (d, J=9.0 Hz, 2H), 3.93 (m, 2H), 2.73 (m, 2H),2.53 (m, 4H), 0.96 (t, J=7.0 Hz, 4H). Anal. Calcd. forC₂₆H₂₅NO₄S.0.5H₂O: C, 68.40; H, 5.74; N, 3.07. Found: C, 68.52; H, 6.00;N, 3.34.

EXAMPLE 11

[0143] Preparation of[6-Hydroxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[0144] The title compound was prepared from the product of Example 4 ina manner similar to that employed in Example 7 above; mp 125-130° C. ¹HNMR (DMSO-d₆) d 9.75 (s, 1H), 9.71 (s, 1H), 7.50 (d, J=9.0 Hz, 2H), 7.26(d, J=2.0 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 6.85 (s, 3H), 6.80 (dd,J=9.0, 2.0 Hz, 1H), 6.79 (d, J=9.0 Hz), 3.94 (t, J=6.0 Hz, 2H), 2.80 (t,J=6.0 Hz, 2H), 2.66 (m, 4H), 1.53 (m, 8H). Anal. Calcd. for C₂₈H₂₉NO₄S:C, 70.71; H, 6.15; N, 2.94. Found: C, 70.67; H, 6.31; N, 2.93.

EXAMPLE 12

[0145] Preparation of[6-Hydroxy-3-[4-[2-(1-N,N-diethylamino)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[0146] The title compound was prepared from the product of Example 5 ina manner similar to that employed in Example 7 above; mp 137-141° C. ¹HNMR (DMSO-d₆) d 9.75 (s, 1H), 9.71 (s, 1H), 7.49 (d, J=9.0 Hz, 1H), 7.25(d, j=2.0 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 6.85 (s, 4H), 6.80 (dd,J=9.0, 2.0 Hz, 1H), 6.79 (d, J=9.0 Hz, 2H), 3.95 (t, J=6.0 Hz, 2H), 2.74(t, J=6.0 Hz, 2H), 2.51 (m, 4H), 1.66 (m, 6H). Anal. Calcd. forC₂₆H₂₇NO₄S: C, 69.46; H, 6.05; N, 3.12. Found: C, 69.76; H, 5.85; N,3.40.

EXAMPLE 13

[0147] Preparation of[6-Hydroxy-3-[4-[2-(morpholino)ethoxy]-phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiopheneHydrochloride

[0148] The title compound was prepared from the product of Example 6 ina manner similar to that employed in Example 7 above; mp 157-162° C. ¹HNMR (DMSO-d₆) d 10.60 (bs, 1H), 9.80 (s, 1H), 9.75 (s, 1H), 7.50 (d,J=9.0 Hz, 2H), 7.28 (d, J=2.0 Hz, 1H), 7.10 (d, J=9.0 Hz, 1H), 6.92 (q,J_(AB)=9.0 Hz, 4H), 6.81 (dd, J=9.0, 2.0 Hz, 1H), 6.80 (d, J=9.0 Hz,2H), 4.30 (m, 2H), 3.95 (m, 2H), 3.75 (m, 2H), 3.51 (m, 4H), 3.18 (m,2H). Anal. Calcd. for C₂₆H₂₅NO₅S-HCl: C, 62.46; H, 5.24; N, 2.80. Found:C, 69.69; H, 5.43; N, 2.92.

EXAMPLE 14

[0149] Preparation of[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[0150] Step a): Preparation of 6-Methoxybenzo[b]thiophene-2-boronic Acid

[0151] To a solution of 6-methoxybenzo[b]thiophene (18.13 g, 0.111 mol)in 150 mL of anhydrous tetrahydrofuran (THF) at −60° C. was addedn-butyllithium (76.2 mL, 0.122 mol, 1.6 M solution in hexanes), dropwisevia syringe. After stirring for 30 minutes, triisopropyl borate (28.2mL, 0.122 mol) was introduced via syringe. The resulting mixture wasallowed to gradually warm to 0° C. and then distributed between 1Nhydrochloric acid and ethyl acetate (300 mL each). The layers wereseparated, and the organic layer was dried over sodium sulfate.Concentration in vacuo produced a white solid that was triturated fromethyl ether hexanes. Filtration provided 16.4 g (71%) of6-methoxybenzo[b] thiophene-2-boronic acid as a white solid. mp 200° C.(dec). ¹H NMR (DMSO-d₆) d 7.83 (s, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.51 (d,J=2.0 Hz, 1H), 6.97 (dd, J=8.6, 2.0 Hz, 1H), 3.82 (s, 3H). FD mass spec:208.

[0152] Step b): Preparation of[6-Methoxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]thiophene

[0153] To a solution of 6-methoxybenzo[b]thiophene-2-boronic acid (3.00g, 14.4 mmol) in 100 mL of toluene was added4-(methanesulfonyloxy)phenylbromide (3.98 g, 15.8 mmol) followed by 16mL of 2.0 N sodium carbonate solution. After stirring for 10 minutes,tetrakistriphenylphosphinepalladium (0.60 g, 0.52 mmol) was added, andthe resulting mixture was heated to reflux for 5 hours. The reactionmixture was then allowed to cool to ambient temperature whereupon theproduct precipitated from the organic phase. The aqueous phase wasremoved and the organic layer was concentrated in vacuo to a solid.Trituration from ethyl ether yielded a solid that was filtered and driedin vacuo to provide 3.70 g (77%) of[6-methoxy-2-(4-methanesulfonyloxy-phenyl)]benzo[b]thiophene as a tansolid. mp 197-201° C. ¹H NMR (DMSO-d₆) d 7.82-7.77 (m, 3H), 7.71 (d,J=8.8 Hz, 1H), 7.54 (d, J=2.3 Hz, 1H), 7.40 (d, J=8.7 Hz, 2H), 6.98 (dd,J=8.7, 1.5 Hz, 1H), 3.80 (s, 3H), 3.39 (s, 3H). FD mass spec 334. Anal.Calcd. for C₁₆H₁₄O₄S₂: C, 57.46; H, 4.21. Found: C, 57.76; H, 4.21.

[0154] Step c): Preparation of[6-Hydroxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]thiophene

[0155] To a solution of[6-methoxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]thiophene (9.50 g,28.40 mmol) in anhydrous methylene chloride (200 mL) at room undernitrogen gas was added boron tribromide (14.20 g, 5.36 mL, 56.8 mmol).The resulting mixture was stirred at ambient temperature for 3 hours.The reaction was quenched by slowly pouring into excess ice water. Aftervigorously stirring for 30 minutes, the white precipitate was collectedby filtration, washed several times with water, and then dried in vacuoto provide 8.92 g (98%) of [6-hydroxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]thiophene as a white solid. mp 239-243° C. ¹H NMR (DMSO-d₆) d9.70 (s, 1H), 7.76 (d, J=8.7 Hz, 2H), 7.72 (s, 1H), 7.62 (d, J=8.7 Hz,1H), 7.38 (d, J=8.7 Hz, 2H), 7.24 (d, J=1.7 Hz, 1H), 6.86 (dd, J=8.7,1.7 Hz, 1H), 3.38 (s, 3H). FD mass spec 320. Anal. Calcd. forC₁₅H₁₂O₄S₂: C, 56.23; H, 3.77. Found: C, 56.49; H, 3.68.

[0156] Step d): Preparation of[6-Benzyloxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]thiophene

[0157] To a solution of[6-hydroxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]thiophene (3.20 g,10.0 mmol) in 75 mL of anhydrous DMF was added Cs₂CO₃ (5.75 g, 17.7mmol) followed by benzylchloride (1.72 mL, 11.0 mmol). The resultingmixture was stirred vigorously for 24 hours. The solvent was removed invacuo, and the solid residue was suspended in 200 mL of water. The whiteprecipitate was collected by filtration and washed several times withwater. Upon drying in vacuo, the crude product was suspended in 1:1hexanes:ethyl ether. The solid was collected to provide 3.72 g (91%) of[6-benzyloxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]thiophene as a whitesolid. mp 198-202° C. ¹H NMR (DMSO-d₆) d 7.81-7.78 (m, 3H), 7.72 (d,J=8.7 Hz, 1H), 7.64 (d, J=2.2 Hz, 1H), 7.47-7.30 (m, 7H), 5.15 (s, 2H),3.39 (s, 3H). FD mass spec 410.

[0158] Step e): Preparation of[6-Benzyloxy-2-(4-hydroxyphenyl)]-benzo[b]thiophene

[0159] To a solution of[6-benzyloxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]thiophene (12.50 g,30.50 mmol) in 300 mL of anhydrous THF under nitrogen gas at ambienttemperature was added lithium aluminum hydride (2.32 g, 61.0 mmol) insmall portions. The mixture was then stirred at ambient temperature for3 hours and then quenched by carefully pouring the mixture into anexcess of cold 1.0 N hydrochloric acid. The aqueous phase was extractedwith ethyl acetate. The organic was then washed several times with waterand then dried (sodium sulfate) and concentrated in vacuo to a solid.Chromatography (silicon dioxide, chloroform) provided 8.75 g (87%) of[6-benzyloxy-2-(4-hydroxyphenyl)]benzo[b] thiophene as a white solid. mp212-216° C. ¹H NMR (DMSO-d₆) d 9.70 (s, 1H), 7.63 (d, J=8.7 Hz, 1H),7.56 (d, J=2.2 Hz, 1H), 7.51-7.30 (m, 8H), 7.00 (dd, J=8.7, 2.2 Hz, 1H),6.80 (d, J=8.6 Hz, 2H), 5.13 (s, 2H). FD mass spec 331. Anal. Calcd. forC₂₁H₁₆O₂S: C, 75.88; H, 4.85. Found: C, 75.64; H, 4.85.

[0160] Step f): Preparation of[6-Benzyloxy-2-(4-methoxyphenyl)]-benzo[b]thiophene

[0161] To a solution of [6-benzyloxy-2-(4-hydroxyphenyl)]benzo[b]thiophene (8.50 g, 26.40 mmol) in 200 mL of anhydrous DMF undernitrogen gas at ambient temperature was added sodium hydride (1.66 g,41.5 mmol) in small portions. Once gas evolution had ceased, iodomethane(3.25 mL, 52.18 mmol) was added dropwise. The reaction was stirred for 3hours at ambient temperature. The solvent was then removed in vacuo, andthe residue distributed between water/ethyl acetate. The layers wereseparated, and the organic phase was washed several times with water.The organic layer was then dried (sodium sulfate) and concentrated invacuo to provide 9.00 g (98%) of [6-benzyloxy-2-(4-methoxyphenyl)]benzo[b]thiophene as a white solid. mp 180-185° C. ¹H NMR (DMSO-d₆) d7.67-7.58 (m, 5H), 7.46-7.29 (m, 5H), 7.02 (dd, J=8.8, 2.2 Hz, 1H), 6.98(d, J=8.7 Hz, 2H), 5.13 (s, 2H), 3.76 (s, 3H). FD mass spec 346. Anal.Calcd. for C₂₂H₁₈O₂S: C, 76.27; H, 5.24. Found: C, 76.54; H, 5.43.

[0162] Step g): Preparation of[6-Benzyloxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene

[0163] [6-Benzyloxy-2-(4-methoxyphenyl)]benzo[b]thiophene (10.0 g, 28.9mmol) was placed in 200 mL of chloroform along with 10.0 g of solidsodium bicarbonate at ambient temperature. To this suspension was addedbromine (1.50 mL, 29.1 mmol) dropwise over 30 minutes as a solution in100 mL of chloroform. Upon completion of the addition, water (200 mL)was added and the layers were separated. The organic phase was dried(sodium sulfate) and concentrated in vacuo to a white solid.Crystallization from methylene chloride/methanol provided 10.50 g (85%)of [6-benzyloxy-2-(4-methoxyphenyl)-3-bromo]benzo-[b]thiophene as awhite solid. mp 146-150° C. ¹H NMR (DMSO-d₆) d 7.70 (d, J=2.2 Hz, 1H),7.65-7.60 (m, 3H), 7.47-7.30 (m, 5H), 7.19 (dd, J=8.8, 2.2 Hz, 1H), 7.06(d, J=8.7 Hz, 2H), 5.17 (s, 2H), 3.78 (s, 3H). FD mass spec 346. Anal.Calcd. for C₂₂H₁₇O₂SBr: C, 62.13; H, 4.03. Found: C, 61.87; H, 4.00.

[0164] Step h): Preparation of[6-Benzyloxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide)

[0165] The title compound was prepared by oxidation of the product fromstep g) with 1.5 equivalents of hydrogen peroxide in a mixture oftrifluoroacetic acid in methylene chloride. The product was isolated asa yellow solid by crystallization from ethyl acetate. mp 202-205° C. ¹HNMR (DMSO-d₆) d 7.80 (d, J=2.2 Hz, 1H), 7.68 (d, J=8.7 Hz, 2H), 7.55(d,J=8.4 Hz, 1H) 7.47-7.32 (m, 6H), 7.10 (d, J=8.7 Hz, 2H), 5.23 (s, 2H),3.80 (s, 3H). FD mass spec 441. Anal. Calcd. for C₂₂H₁7O₃SBr: C, 59.87;H, 3.88. Found: C, 59.59; H, 3.78.

[0166] Step i): Preparation of[6-Benzyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]-benzo[b]thiophene-(S-oxide)

[0167] Reaction of the product of step i) above with4-(2-piperidinoethoxy)phenol in base yielded the title compound as ayellow oil. ¹H NMR (DMSO-d₆) d 7.76 (d, J=2.2 Hz, 1H), 7.62 (d, J=8.8Hz, 2H), 7.44-7.30 (m, 5H), 7.12 (dd, J=8.6, 2.2 Hz, 1H), 7.03-6.93 (m,5H), 6.85 (d, J=8.8 Hz, 2H), 5.18 (s, 2H), 3.94 (bt, J=5.8 Hz, 2H), 3.73(s, 3H), 2.56 (bt, J=5.8 Hz, 2H), 2.37-2.34 (m, 4H), 1.45-1.32 (m, 6H).FD mass spec 592. Anal. Calcd. for C₃₅H₃₅NO₅S: C, 72.26; H, 6.06; N,2.41. Found: C, 72.19; H, 5.99; N, 2.11.

[0168] Step j): Preparation of[6-Benzyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]-benzo[b]thiophene

[0169] Reduction of the product of step i) above yielded the titlecompound, isolated in 95% overall yield. Purification by chromatography(SiO₂, 1-5% methanol/chloroform) provided an off-white solid, mp105-108° C. ¹H NMR (DMSO-d₆) d 7.62 (d, J=2.2 Hz, 1H), 7.59 (d, J=8.8Hz, 2H), 7.45-7.30 (m, 5H), 7.15 (dd, J=8.6 Hz, 1H), 7.00-6.94 (m, 3H),6.82 (s, 4H), 5.13 (s, 2H), 3.92 (bt, J=5.8 Hz, 2H), 3.72 (s, 3H), 2.55(bt, J=5.8 Hz, 2H), 2.37-2.34 (m, 4H), 1.44-1.31 (m, 4H). FD mass spec565. Anal. Calcd. for C₃₅H₃₅NO₄S: C, 74.31; H, 6.24; N, 2.48. Found: C,74.35; H, 6.07; N, 2.76.

[0170] Step k): Preparation of[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]-thiophene

[0171] To a solution of [6-benzyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene (8.50 g, 15.0mmol) in 300 mL of 5:1 ethanol/ethyl acetate was added palladium black(1.50 g), ammonium formate (3.50 g, 55.6 mmol), and 30 mL of water. Theresulting mixture was heated to reflux and monitored by TLC. Afterapproximately 3 hours, the reaction was judged complete and the solutionwas cooled to ambient temperature. The reaction was filtered through apad of Celite to remove catalyst, and the filtrate was concentrated invacuo to a solid. The concentrate was distributed between saturatedsodium bicarbonate solution and 5% ethanol/ethyl acetate. The layerswere separated, and the organic phase was dried (sodium sulfate) andconcentrated in vacuo. The crude product was chromatographed (silicondioxide, 1-5% methanol/chloroform) to provide 6.50 g (91%) of[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene as foam thatconverted to solid upon trituration with hexanes. mp 174-176° C. ¹H NMR(DMSO-d₆) d 9.77 (s, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.23 (d, J=2.0 Hz,1H), 7.07 (d, J=8.6 Hz, 1H), 6.93 (d, J=8.8 Hz, 2H), 6.81 (s, 4H), 6.76(dd, J=8.6, 2.0 Hz, 1H), 3.91 (bt, J=5.9 Hz, 2H), 3.71 (s, 3H), 2.55(bt, J=5.9 Hz, 2H), 2.38-2.33 (m, 4H), 1.46-1.28 (m, 6H). FD mass spec475. Anal. Calcd. for C₂₈H₂₉NO₄S: C, 70.71; H, 6.15; N, 2.94. Found: C,70.46; H, 5.93; N, 2.71.

EXAMPLE 15

[0172] Preparation of[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiopheneHydrochloride Salt

[0173] The product of Example 14 was converted to the correspondinghydrochloride salt in 85% yield by treatment with a mixture of HClsaturated diethyl ether in ethyl acetate followed by crystallizationfrom ethanol/ethyl acetate; mp 156-160° C. ¹H NMR (DMSO-d₆) d 10.28 (bs,1H), 9.85 (s, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.25 (d, J=2.0 Hz, 1H), 7.06(d, J=8.7 Hz, 1H), 6.93 (d, J=8.8 Hz, 2H), 6.87 (q, J_(AB)=9.3 Hz, 4H),4.27 (bt, J=5.9 Hz, 2H), 3.71 (s, 3H), 3.44-3.31 (m, 4H), 2.98-2.88 (m,2H), 1.74-1.60 (m, 5H), 1.36-1.29 (m, 1H) FD mass spec 475. Anal. Calcd.for C₂₈H₂₉NO₄S.1.0HCl: C, 65.68; H, 5.90; N, 2.73. Found: C, 65.98; H,6.11; N, 2.64.

EXAMPLE 16

[0174] Preparation of[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[0175] Step a): Preparation of[6-methoxy-2-(4-benzyloxyphenyl)]-benzo[b]thiophene

[0176] Following the general procedures of steps a) through g) ofExample 14, the title compound was obtained in 73% yield, mp 217-221° C.¹H NMR (DMSO-d₆) d 7.63-7.60 (m, 3H), 7.59-7.26 (m, 7H), 7.02 (d, J=8.7Hz, 2H), 6.96 (dd, J=8.8, 2.2 Hz, 1H), 5.11 (s, 2H), 3.88 (s, 3H). FDmass spec 346. Anal. Calcd. for C₂₂H₁₈O₂S: C, 76.27; H, 5.24. Found: C,76.00; H, 5.25.

[0177] Step b):[6-methoxy-2-(4-benzyloxyphenyl)-3-bromo]benzo-[b]thiophene

[0178] The title compound was obtained in 91% yield, mp 125-127° C. ¹HNMR (DMSO-d₆) d 7.64-7.61 (m, 4H), 7.46-7.31 (m, 5H), 7.15-7.09 (m, 3H),5.15 (s, 2H), 3.82 (s, 3H). FD mass spec 346. Anal. Calcd. forC₂2H₁₇O₂SBr: C, 62.13; H, 4.03. Found: C, 62.33; H, 3.93.

[0179] Step c):[6-Methoxy-2-(4-benzyloxyphenyl)-3-bromo]benzo[b]-thiophene-(S-oxide)

[0180] The title compound was isolated as a yellow solid bychromatography (SiO₂, CHCl₃). mp 119-123° C. ¹H NMR (DMSO-d₆) d 7.73 (d,J=2.2 Hz, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.5 Hz, 1H) 7.46-7.31(m, 5), 7.26 (dd, J=8.5, 2.2 Hz, 1H), 7.18 (d, J=8.8 Hz, 2H), 5.16 (s,2H), 3.86 (s, 3H). FD mass spec 441. Anal. Calcd. for C₂₂H₁₇O₃SBr: C,59.87; H, 3.88. Found: C, 60.13; H, 4.10.

[0181] Step d):[6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene-(S-oxide)

[0182] The title compound was obtained as a yellow solid, mp 89-93° C.¹H NMR (DMSO-d₆) d 7.68 (d, J=2.2 Hz, 1H), 7.62 (d, J=8.8 Hz, 2H),7.42-7.28 (m, 5H), 7.08-6.92 (m, 6H), 6.86 (d, J=8.8 Hz, 2H), 5.09 (s,2H), 3.94 (bt, J=5.8 Hz, 2H), 3.81 (s, 3H), 2.56 (bt, J=5.8 Hz, 2H),2.37-2.34 (m, 4H), 1.45-1.31 (m, 6H). FD mass spec 592. Anal. Calcd. forC₃₅H₃₅NO₅S.0.25EtOAc: C, 71.62; H, 6.18; N, 2.32. Found: C, 71.32; H,5.96; N, 2.71.

[0183] Step e):[6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene

[0184] The title compound was obtained in 91% yield, mp 106-110° C. ¹HNMR (DMSO-d₆) d 7.59 (d, J=8.8 Hz, 2H), 7.54 (d, J=2.2 Hz, 1H),7.42-7.28 (m, 5H), 7.13 (d, J=8.8 Hz, 1H), 7.03 (d, J=8.8 Hz, 2H), 6.82(s, 4H), 5.08 (s, 2H), 3.92 (bt, J=5.8 Hz, 2H), 3.78 (s, 3H), 2.55 (bt,J=5.8 Hz, 2H), 2.37-2.33 (m, 4H), 1.44-1.31 (m, 4H). FD mass spec 565.Anal. Calcd. for C₃₅H₃₅NO₄S: C, 74.31; H, 6.24; N, 2.48. Found: C,74.26; H, 6.17; N, 2.73.

[0185] Step f): Preparation of[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[0186] The title compound was obtained in 88% yield, mp 147-150° C. ¹HNMR (DMSO-d₆) d 9.72 (s, 1H), 7.51 (d, J=2.0 Hz, 1H), 7.48 (d, J=8.6 Hz,2H), 7.11 (d, J=8.8 Hz, 1H), 6.88 (dd, J=8.8, 2.2 Hz, 1H), 6.81 (s, 4H),6.76 (d, J=8.6, 2H), 3.91 (bt, J=5.9 Hz, 2H), 3.77 (s, 3H), 2.55 (bt,J=5.9 Hz, 2H), 2.38-2.33 (m, 4H), 1.46-1.28 (m, 6H). FD mass spec 475.Anal. Calcd. for C₂₈H₂₉NO₄S: C, 70.71; H, 6.15; N, 2.94. Found: C,71.00; H, 6.17; N, 2.94.

EXAMPLE 17

[0187] Preparation of[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiopheneHydrochloride

[0188] The title compound was prepared in a manner analogous to thatemployed in Example 15 to yield the title compound, mp 215-217° C. ¹HNMR (DMSO-d₆) d 10.28 (bs, 1H), 9.80 (s, 1H), 7.52 (d, J=2.2 Hz, 1H),7.47 (d, J=8.6 Hz, 2H), 7.12 (d, J=8.4 Hz, 1H), 6.91-6.80 (m, 5H), 6.78(d, J=8.6 Hz, 2H), 4.27 (bt, J=5.8 Hz, 2H), 3.78 (s, 3H), 3.43-3.34 (m,4H), 2.97-2.91 (m, 2H), 1.78-1.61 (m, 5H), 1.36-1.29 (m, 1H). FD massspec 475. Anal. Calcd. for C₂₈H₂₉NO₄S.1.0HCl: C, 65.68; H, 5.90; N,2.73. Found: C, 65.87; H, 5.79; N, 2.99.

FORMULATION EXAMPLES

[0189] In the formulations which follow, “active ingredient” means acompound of formula I, or a salt or solvate thereof. Formulation Example1 Gelatin Capsules Ingredient Quantity (mg/capsule) Active ingredient0.1-1000  Starch, NF 0-650 Starch flowable powder 0-650 Silicone fluid350 centistokes 0-15  Formulation Example 2 Tablets Ingredient Quantity(mg/tablet) Active ingredient 2.5-1000  Cellulose, microcrystalline200-650  Silicon dioxide, fumed 10-650  Stearate acid 5-15  FormulationExample 3 Tablets Ingredient Quantity (mg/tablet) Active ingredient25-1000 Starch 45 Cellulose, microcrystalline 35 Polyvinylpyrrolidone 4(as 10% solution in water) Sodium carboxymethyl cellulose 4.5 Magnesiumstearate 0.5 Talc 1

[0190] The active ingredient, starch, and cellulose are passed through aNo. 45 mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 60 U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yieldtablets. Formulation Example 4 Suspensions Ingredient Quantity (mg/5 ml)Active ingredient 0.1-1000 mg Sodium carboxymethyl cellulose 50 mg Syrup1.25 mg Benzoic acid solution 0.10 mL Flavor q.v. Color q.v. Purifiedwater to 5 mL

[0191] The medicament is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor, and color are diluted withsome of the water and added, with stirring. Sufficient water is thenadded to produce the required volume. Formulation Example 5 AerosolQuantity (% by Ingredient weight) Active ingredient 0.25 Ethanol 25.75Propellant 22 (Chlorodifluoromethane) 70.00

[0192] The active ingredient is passed through a No. 60 mesh U.S. sieveand suspended in the saturated fatty acid glycerides previously meltedusing the minimal necessary heat. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.Formulation Example 6 Suppositories Ingredient Quantity (mg/suppository)Active ingredient 250 Saturated fatty acid glycerides 2,000

[0193] Formulation Example 7 Injectable Formulations Ingredient QuantityActive ingredient   50 mg Isotonic saline 1,000 mL

[0194] The solution of the above ingredients is intravenouslyadministered to a patient at a rate of about 1 mL per minute.

We claim:
 1. The use of a compound having the structure

or a pharmaceutically acceptable salt or pro-drug thereof, wherein R¹and R² are independently selected from the group consisting of hydroxyand alkoxy of one to four carbon atoms; and R³ and R⁴ are independentlyselected from methyl or ethyl, or R³ and R⁴, taken together with thenitrogen atom to which they are attached, form a pyrrolidino,methylpyrrolidino, dimethylpyrrolidino, piperidino, morpholino, orhexamethyleneimino ring; in the preparation of a medicament useful fortreating a central nervous system disorder selected from depression,mood swings, and Alzheimer's disease in a patient.
 2. The use of claim 1wherein said medicament is useful for treating depression or moodswings.
 3. The use of claim 1 wherein said medicament is useful fortreating Alzheimer's disease.
 4. The use of claim 1 wherein R¹ and R²are both hydroxy.
 5. The use of claim 2 wherein R¹ and R² are bothhydroxy.
 6. The use of claim 3 wherein R¹ and R² are both hydroxy. 7.The use of claim 1 wherein R¹ is hydroxy and R² is alkoxy of one to fourcarbon atoms.
 8. The use of claim 2 wherein R¹ is hydroxy and R² isalkoxy of one to four carbon atoms.
 9. The use of claim 3 wherein R¹ ishydroxy and R² is alkoxy of one to four carbon atoms.
 10. The use ofclaim 1 wherein R³ and R⁴ combine with the nitrogen atom to which theyare attached to form a piperidino ring.
 11. The use of claim 2 whereinR³ and R⁴ combine with the nitrogen atom to which they are attached toform a piperidino ring.
 12. The use of claim 3 wherein R³ and R⁴ combinewith the nitrogen atom to which they are attached to form a piperidinoring.
 13. The use of a compound having the structure

or a pharmaceutically acceptable salt or pro-drug thereof, wherein R² ishydroxy or methoxy; in the preparation of a medicament useful fortreating depression or mood swings in a patient.
 14. The use of claim 13wherein said compound is6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy)phenoxy]benzo[b]thiopheneor a pharmaceutically acceptable salt thereof.
 15. The use of claim 13wherein said compound is6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)phenoxy]benzo[b]thiopheneor a pharmaceutically acceptable salt thereof.
 16. The use of a compoundhaving the structure

or a pharmaceutically acceptable salt or pro-drug thereof, wherein R² ishydroxy or methoxy; in the preparation of a medicament useful fortreating Alzheimer's disease in a patient.
 17. The use of claim 16wherein said compound is6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy)phenoxy]benzo[b]thiopheneor a pharmaceutically acceptable salt thereof.
 18. The method of claim16 wherein said compound is6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)phenoxy]benzo[b]thiopheneor a pharmaceutically acceptable salt thereof.
 19. The use of claim 13wherein said salt is the hydrochloride salt.
 20. The use of claim 16wherein said salt is the hydrochloride salt.